P837: MULTIPLE MYELOMA AND ADJACENT NK CELLS CAN EXPRESS THE MACHINERY TO INTEGRATE NEURONAL SIGNALS
Authors: Ana Filipa Barahona, Roel Klein Wolterink, Antonio Galzerano, Emilie Carneiro, Joana Caetano, Bruna Velosa Ferreira, Ana Queirós, Cristina João
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Multiple Myeloma (MM) is characterised by the accumulation of monoclonal plasma cells in a dynamic and permissive bone marrow (BM) microenvironment. Most immune cells express neuronal receptors and neurotransmitters, allowing the crosstalk between these multicellular networks. Interactions between neurons and immune cells have been reported to regulate organ physiology and contribute to several cancers. NK cells are important players in MM, and adrenergic signals were shown to directly influence NK function. Furthermore, retrospective clinical studies show that MM patients under β-adrenergic receptor blockers have a significantly improved prognosis and overall survival. However, MM-neuronal interaction, especially in the suppressive tumour microenvironment, remains poorly understood. Aims: To unravel how neuronal innervation is altered in MM BM microenvironment and how neuronal interactions directly influence MM function and immune cells infiltration in the tumour microenvironment. Methods: Immunohistochemistry was used to characterise and quantify neuronal fibres in BM biopsies of newly diagnosed MM patients and controls (n=5 + 5). Expression of a pan-neuronal marker (TUBB3), and specific markers for adrenergic (TH) and cholinergic (VAChT) neurons were scored. BM patients’ biopsies without disease infiltration were used as controls. Publicly available scRNAseq datasets of MM-infiltrating immune cells and controls were used to determine the transcription of genes encoding the machinery to integrate neuronal signals. NK cells from samples of newly diagnosed MM and control patients (n=13 + 7) were identified using R software and transcribed receptors for neuronal signals were determined. Results: We observed a two-fold increase in neuronal fibres in MM patients compared to controls. Like in BM from healthy controls, MM BM was mainly innervated by adrenergic (TH+) fibres (Fig1). Interestingly, 1,2% of MM cells transcribed ADRB2 receptor for adrenaline, the main sympathetic neurotransmitter, in contrast to 0% in BM control plasma cells. Furthermore, MM cells extensively transcribed GRIK4 in 3,9% (19,5-fold) compared to normal plasma cells from controls. Glutamate, the major excitatory neurotransmitter, has been described to induce B cell proliferation and Ig production. NK cells were the main population expressing neuronal adrenergic receptors. ADRB1 and ADRB2 were present in 2.1% vs 4.5% respectively, of total NK cells within the BM of MM patients in comparison to controls (0,8% vs 3,4%). MM patients have a 2.6-fold ADRB1 and ADRB2 1.3-fold increase compared to control, supporting the idea that adrenalin influences NK cells function via adrenergic receptors in MM BM niche. In addition, the population of CD38neg NK cells, a residual NK subpopulation displaying a high proliferative potential and functional antitumor activity, was slightly more abundant in control BM (48,7% of total NK cells vs 42,2% in MM BM). ADRB2 transcription in this cell subset was higher in MM patients vs control (10,1% vs 7,7%). Taken together, results suggest that BM from MM patients have a disadvantageous NK profile and are more susceptible to influence of adrenergic activity. Summary/Conclusion: MM Patients’ BM is more innervated than controls due to sympathetic contribution. A higher number of sympathetic fibres and a consequent increase of adrenaline/noradrenaline production may trigger the transcription of adrenergic receptors in MM and NK cells. These discrete yet important results, may reflect the differences of spatial distribution of MM and the adjacent and remote immune and neuronal cells in the BM.Keywords: Multiple myeloma, Neural, NK cell, Gene transcription